Cutaneous T-cell lymphoma (CTCL) is a lymphoproliferative disorder typically characterized by infiltration of the skin with clonally derived malignant CD4+ T lymphocytes that phenotypically resemble mature T cells (Diamandidou, E. et al. 1996. Blood 88:2385–2409). Early presentation of the disease may be confused with eczema, tinea corpus, or psoriasis. Therapeutic efforts are based on the extent of disease, the integrity of the immune system, and the likelihood for progression of disease. Several additional observations which can effect therapeutic decisions include 1) antitumor immune responses mediated by cytotoxic T cells detected in patients with CTCL, 2) biologic response modifiers, which can augment cytotoxic T-cell responses with other specific arms of the antitumor response, such as recombinant interferon-α, are therapeutically active in CTCL, and 3) combinations of potent chemotherapeutic agents do not appear to cure patients with early disease and do not prolong the survival of patients with advanced disease.
For patients with limited or early stage disease, the cell-mediated immune response is usually normal, and the likelihood for serious systemic disease progression is low. Accordingly, these patients can be treated effectively with a variety of skin-based therapies, including topical mechlorethamine, topical carmustine, and psoralen and ultraviolet A light (PUVA). A significant percentage of patients with such early disease appear to be cured of their disease with these treatments.
Advanced forms of CTCL are not as easily cured, and are often fatal. The patient with advanced forms of CTCL may present with malignancies that progress from plaques to tumors. A more common form of advanced CTCL, Sezary Syndrome (SzS), involves erythroderma occurring throughout the course of disease. In SzS, the malignant cell population, which has an early propensity to localize within the upper dermis, and particularly, within the epidermis (epidermotropism), also becomes nonepidermotropic and is associated with deeper dermal extension and involvement of the peripheral blood. Concurrent with this leukemic, progressive phase of the disease is the onset of progressive immunologic dysfunction. Among the constellation of immune abnormalities that have been noted are increased serum IgE, decreased T cell responses to antigens, impaired cellular cytotoxicity, and peripheral eosinophilia. Associated with these immune abnormalities is a striking deficiency in the ability of peripheral blood mononuclear cells (PBMC) to produce interferon-γ and interleukin-2 in response to activation signals (Rook, A. H. et al. 1993. Arch. Dermatol. 129:486; Vowels, B. R. et al. 1992. J. Invest. Dermatol. 99:90). In contrast to a defect in production of T-helper type 1 (Th1) cytokines, upon stimulation, PBMC from patients with SzS produce increased concentrations of interleukin-4, the levels of which correlate with numbers of circulating malignant T cells (Vowels, B. R. et al. 1992. J. Invest. Dermatol. 99:90). The ability to detect T-helper type 2 (Th2) cytokine mRNA (mRNA for interleukin-4 and interleukin-5) in skin lesions of patients with CTCL, but not in normal skin (Vowels, B. R. et al. 1994. J. Invest. Dermatol. 103:669) suggests that the malignant Th cells in CTCL may be derived from the Th2 subpopulation of CD4+ cells.
Recent studies have shown that excess interleukin-4 production by PBMCs from SzS patients can be inhibited in vitro either by interferon-γ or by interferon-α (Vowels, B. R. et al. 1992. J. Invest. Dermatol. 99:90). Moreover, SzS patients who develop complete remission associated with the disappearance of detectable malignant peripheral blood cells during therapy with biologic response modifiers, including interferon-α, have restored a normal pattern of cytokine production by their PBMC in concert with the normalization of many immune parameters (Vowels, B. R. et al. 1993. J. Invest. Dermatol. 100:556). Therefore, strategies directed simultaneously at affecting the cytokine imbalance and impeding proliferation of the malignant T cell population may have a beneficial effect on the outcome of this frequently fatal disorder.
Interleukin-12 (IL-12) is a cytokine that is a powerful inducer of interferon-γ production and that exerts potent Th1 inducing effects during the evolution of immunologic responses against certain microbial antigens (Chan, S. H. et al. 1991. J. Exp. Med. 173:869–879; Hsieh, C. S. et al. 1993. Science 260:547–549). IL-12 augments Natural Killer (NK) cell cytotoxicity and cytotoxic T cell proliferation and function (Hiramatsu, K. et al. 1998. Cancer Immunol. Immunother. 46:1–6; Haku, T. et al. 1997. Cytokine 9:846–852; Sahin, U. et al. 1996. Cancer Immunol. Immunother. 42:9–1), activities that may be beneficial in regard to the abnormal Th2 clonal proliferation observed in advanced CTCL, including SzS. Studies have shown that PBMCs isolated from patients with advanced CTCL exhibit marked defects in the production of IL-12 (Rook, A. H. et al. 1997. Clin. Exp. Immunol. 107:16–20; Seo, N. et al. 1998. Clin. Exp. Immunol. 112:403–409). Further, IL-12 has been shown to have potent antitumor activity in mice with transplantable and primary tumors (Nishimura et al. 1995. Immunol. Lett. 48:149–152) and in mice with metastatic residual lymphoma (Verbik et al. 1996. Clin. Exp. Metastasis 14:219–229). Brunda and colleagues (1993. J. Exp. Med. 178:1223) have demonstrated antitumor activity of IL-12 in mice following both systemic and intralesional administration.
Recent in vitro experiments have also shown that the depressed interferon-γ production observed in peripheral blood mononuclear cells isolated from patients with advanced CTCL is normalized by the addition of recombinant IL-12. These in vitro studies also showed that the depressed cell-mediated cytotoxicity in CTCL is augmented (Rook, A. H. et al. 1996. Ann. NY Acad. Sci. 795:310–318; Rook et al. 1995. J. Immunol. 154:1491–1498).
It has now been found that advanced CTCL can be successfully treated in humans by in vivo administration of recombinant IL-12.